title: Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions.
abstract: Obesity is an independent risk factor for renal dysfunction in patients with CKDs, including diabetic nephropathy, but the mechanism underlying this connection remains unclear. Autophagy is an intracellular degradation system that maintains intracellular homeostasis by removing damaged proteins and organelles, and autophagy insufficiency is associated with the pathogenesis of obesity-related diseases. We therefore examined the role of autophagy in obesity-mediated exacerbation of proteinuria-induced proximal tubular epithelial cell damage in mice and in human renal biopsy specimens. In nonobese mice, overt proteinuria, induced by intraperitoneal free fatty acid-albumin overload, led to mild tubular damage and apoptosis, and activated autophagy in proximal tubules reabsorbing urinary albumin. In contrast, diet-induced obesity suppressed proteinuria-induced autophagy and exacerbated proteinuria-induced tubular cell damage. Proximal tubule-specific autophagy-deficient mice, resulting from an Atg5 gene deletion, subjected to intraperitoneal free fatty acid-albumin overload developed severe proteinuria-induced tubular damage, suggesting that proteinuria-induced autophagy is renoprotective. Mammalian target of rapamycin (mTOR), a potent suppressor of autophagy, was activated in proximal tubules of obese mice, and treatment with an mTOR inhibitor ameliorated obesity-mediated autophagy insufficiency. Furthermore, both mTOR hyperactivation and autophagy suppression were observed in tubular cells of specimens obtained from obese patients with proteinuria. Thus, in addition to enhancing the understanding of obesity-related cell vulnerability in the kidneys, these results suggest that restoring the renoprotective action of autophagy in proximal tubules may improve renal outcomes in obese patients.
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan;
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamahara
authors.forename: Shinji
authors.initials: S
authors.lastname: Kume
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Yoshikata
authors.initials: Y
authors.lastname: Morita
authors.forename: Masami
authors.initials: M
authors.lastname: Chin-Kanasaki
authors.forename: Hisazumi
authors.initials: H
authors.lastname: Araki
authors.forename: Keiji
authors.initials: K
authors.lastname: Isshiki
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Araki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Haneda
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.forename: Atsunori
authors.initials: A
authors.lastname: Kashiwagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Uzu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress; D004847:Epithelial Cells / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000502:physiology; D009765:Obesity / Q000150:complications*; D011507:Proteinuria / Q000150:complications*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C490981:Gtf2h1 protein, mouse; D046912:Multiprotein Complexes; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases